IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 26. Hypersensitivity - Type IV

GRANULOMATOUS HYPERSENSITIVITY

Granulomatous reactions represent the most clinically significant category of type IV hypersensitivity; they are responsible for many manifestations of DISEASES ASSOCIATED WITH T Cell-mediated immune responses. Typically, granulomatous reactions develop due to the intracellular persistence within macrophages of microorganisms or other particles that The Cell is unable to destroy. Occasionally (e.g., in allergic alveolitis), the persistence of immune complexes is the underlying cause. The reaction results in The formation of an epithelioid cell granuloma.

Histologically, a granulomatous reaction differs sharply from the tuberculin-type reaction. However, both frequently develop upon sensitization by the same microbial Antigens, such as M. tuberculosis and M. leprae (Fig. 26.10). The formation of an immunological granuloma is also observed in hypersensitivity to zirconium and beryllium, as well as in sarcoidosis, although in the latter case the antigen remains unknown. When talc, silica, and numerous other particles enter the body, granulomas contain these inorganic substances. Such non-immunological granulomas can be distinguished by the absence of lymphocytes within them.

Class="center">

Fig. 26.10. The Skin reaction to tuberculin (bottom photo, kindly provided by Prof. J.H.L. Playfair) serves as a clinical diagnostic test for cell-mediated Immunity in tuberculosis. In cases of prolonged antigenic stimulation (rather than a single injection of soluble antigen), a granulomatous reaction develops (top photo, kindly provided by Dr. A. du Vivier) or contact hypersensitivity (middle photo, kindly provided by Dr. D. Sharvill). Such reactions may also occur when macrophages are unable to destroy the antigen.

Granulomatous hypersensitivity reactions are typically characterized by the presence of epithelioid and giant Cells

Epithelioid cells. These large, flattened cells contain a well-developed Endoplasmic reticulum (Fig. 26.11). They are formed from activated macrophages under chronic cytokine stimulation. Continuing to secrete TNF, they thereby enhance inflammation.

Fig. 26.11. Electron micrograph of an epithelioid cell. The presence of such cells is characteristic of a granulomatous hypersensitivity reaction. Compare the extent of The endoplasmic reticulum (E) in an epithelioid cell (1) (x 4800) and in a macrophage (2) (x 4800). (Nu - nucleolus; N - Nucleus; C - Collagen; L - lysosome; M - mitochondrion.) (Photographs kindly provided by M.J. Spencer.)

Giant cells. The fusion of epithelioid cells gives rise to multinucleated giant cells (Fig. 26.12), sometimes referred to as Langhans giant cells (not to be confused with the Langerhans cells described above). Giant cells contain several peripherally (eccentrically) arranged nuclei. They possess a poorly developed Endoplasmic reticulum and degenerating Mitochondria and Lysosomes. Thus, giant cells may represent the terminal stage of Differentiation of the monocyte-macrophage Lineage.

Fig. 26.12. Clinical manifestation and histological picture of the Mitsuda reaction in leprosy on day 28.

1. Skin edema (which may be ulcerated) is much denser and more demarcated than after 48 h.

2. Histological examination reveals a typical epithelioid cell granuloma (hematoxylin and eosin stain; x 60). A giant cell (G) surrounded by lymphocytes is visible in the center of the granuloma. Such a picture is more characteristic of delayed-type hypersensitivity reactions than of the spontaneously resolving tuberculin reaction. The granulomatous reaction is driven by the persistent presence of mycobacterial antigens.

The granuloma contains epithelioid cells, macrophages, and lymphocytes

The center of an immunological granuloma typically contains epithelioid cells and macrophages, sometimes accompanied by giant cells. In certain diseases, such as tuberculosis, a zone of necrosis with complete loss of cellular architecture appears in the central region of the granuloma. The granuloma core, consisting of macrophages and epithelioid cells, is encircled by a zone of lymphocytes; marked fibrosis (deposition of collagen fibers), driven by fibroblast proliferation and enhanced collagen synthesis, may also occur. Examples of granulomatous reactions include the Mitsuda reaction to M. leprae antigens (see Fig. 26.12) and the Kveim test, in which sarcoidosis patients react to (unknown) splenic antigens derived from other sarcoidosis patients. The Features of the three forms of delayed-type hypersensitivity reactions are summarized in Fig. 26.13.

Fig. 26.13. Features of type IV hypersensitivity reactions.